Tissue marker for multimodality radiographic imaging

ABSTRACT

An implantable tissue marker incorporates a contrast agent sealed within a chamber in a container formed from a solid material. The contrast agent is selected to produce a change, such as an increase, in signal intensity under magnetic resonance imaging (MRI). An additional contrast agent may also be sealed within the chamber to provide visibility under another imaging modality, such as computed tomographic (CT) imaging or ultrasound imaging.

RELATED APPLICATIONS

This application is a Continuation-in-Part of U.S. application Ser. No.11/281,801, filed Nov. 17, 2005, and issued as U.S. Pat. No. 7,702,378on Apr. 20, 2010, which is incorporated herein by reference in itsentirety.

TECHNICAL BACKGROUND

The disclosure relates generally to tissue markers. More particularly,the disclosure relates to implantable tissue markers for use in magneticresonance imaging.

BACKGROUND

Certain medical conditions, including breast cancer, are increasinglybeing diagnosed and treated using minimally invasive medical techniques.Such techniques typically involve the use of clinical imaging methodsthat allow the physician to visualize interior portions of a patient'sbody without the need to make excessive incisions or cause avoidablecollateral damage to healthy adjacent tissue. Imaging can be performedusing any of variety of modalities, including, for example, X-rays,computed tomographic (CT) X-ray imaging, fluoroscopy, portal filmimaging devices, electronic portal imaging devices, ultrasound,electrical impedance tomography (EIT), magnetic resonance (MR) imaging,or MRI, magnetic source imaging (MSI), magnetic resonance spectroscopy(MRS), magnetic resonance mammography (MRM), magnetic resonanceangiography (MRA), magnetoelectro-encephalography (MEG), laser opticalimaging, electric potential tomography (EPT), brain electrical activitymapping (BEAM), arterial contrast injection angiography, and digitalsubtraction angiography. Nuclear medicine modalities include positronemission tomography (PET) and single photon emission computed tomography(SPECT).

Some of these imaging procedures involve the use of radiographicmarkers. Radiographic markers are small devices that are implanted in apatient during surgical procedures, such as biopsies. Conventionalmarkers typically consist of one or more solid objects, such as a pieceof metallic wire, ceramic beads, etc., which are implanted either bythemselves or within a gelatinous matrix, collagen, or polylactic acid,to temporarily increase visibility, for example, to ultrasound imaging.They are designed to be visible to one of the imaging modalities listedabove and typically have a shape that is readily identifiable as anartificial structure, as contrasted from naturally occurring anatomicalstructures in the patient's body. For example, markers can be shaped ascoils, stars, rectangles, spheres, or other shapes that do not occur inanatomical structures. Such markers enable radiologists to localize thesite of surgery in subsequent imaging studies or to facilitate imageregistration during image-guided therapeutic procedures. In this way,markers can serve as landmarks that provide a frame of reference for theradiologist.

Most conventional markers appear as a signal void, i.e., a darkartifact, in magnetic resonance imaging. This manifestation can beparticularly problematic in some contexts. For example, heterogeneousbreast tissue produces many dark artifacts under MR imaging, therebyrendering small signal voids produced by some conventional markersdifficult to identify and distinguish from naturally occurring darkartifacts. In addition, some markers produce large susceptibilityartifacts under MR imaging, thereby distorting images in both MRI andspectroscopic modalities. Some markers incorporate an external gel thatmay produce a positive or bright signal, but such gels are notpermanent. Some other markers contain collagen or polylactic acid, whichmay interfere with magnetic resonance spectroscopy. With the increasinguse of MR imaging techniques in the treatment of breast cancer inclinical settings, improved MR visibility of tissue markers isparticularly desirable.

SUMMARY OF THE DISCLOSURE

According to various example embodiments, an implantable tissue markerincorporates a contrast agent sealed within a chamber in a containerformed from a solid material. The contrast agent is selected to producea change in signal intensity under magnetic resonance imaging (MRI). Anadditional contrast agent may also be sealed within the chamber toprovide visibility under another imaging modality, such as computedtomographic (CT) imaging or ultrasound imaging.

One embodiment is directed to a permanently implantable radiographicmarker. A container formed from a solid material defines an internalchamber, in which a contrast agent is sealed. The contrast agent isselected to produce an increase in signal intensity in a magneticresonance (MR) imaging modality. Another embodiment is directed to amethod of manufacturing such a marker.

In another embodiment, a permanently implantable fiducial markerincludes a container formed from a nonbiodegradable solid material. Thecontainer defines an internal chamber. A first contrast agent is sealedwithin the internal chamber and is selected to produce an increase insignal intensity in a magnetic resonance (MR) imaging modality. A secondcontrast agent sealed within the internal chamber. The second contrastagent is selected to produce a signal in another imaging modality.

Another embodiment is directed to a method of identifying a locationwithin a body of a patient. A marker is implanted proximate thelocation. The marker comprises a container formed from a solid materialand defining an internal chamber, and a contrast agent sealed within theinternal chamber. The contrast agent is selected to produce an increasein signal intensity in a magnetic resonance (MR) imaging modality. Afirst image of the location is generated in the magnetic resonance (MR)imaging modality.

Various embodiments may provide certain advantages. For instance, acontrast agent selected to produce an increase in signal intensity in anMR imaging modality may produce good visualization characteristicswithout also producing an excessive artifact and without interferingwith MR spectroscopy or diffusion imaging. Production of an increase insignal intensity in an MR imaging modality may be particularlybeneficial in certain contexts, such as, for example, imaging of breasttissue, which is heterogeneous.

Additional objects, advantages, and features will become apparent fromthe following description and the claims that follow, considered inconjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a sectional view of a tissue marker according to oneembodiment.

FIG. 2 is a sectional view of a tissue marker according to anotherembodiment.

FIG. 3 is a sectional view of a tissue marker according to yet anotherembodiment.

FIG. 4 is an image of the tissue marker of FIG. 1 as visible in amagnetic resonance imaging (MRI) modality.

FIG. 5 is an image of the tissue marker of FIG. 1 as visible in an x-raymammography modality.

FIG. 6 is an image of the tissue marker of FIG. 1 as visible in anultrasound imaging modality.

FIG. 7 is a sectional view of a tissue marker according to anembodiment.

FIG. 8 is a sectional view of a tissue marker according to anembodiment.

DESCRIPTION OF VARIOUS EMBODIMENTS

According to various embodiments, an implantable tissue markerincorporates a contrast agent sealed within a chamber in a containerformed from a solid material. The contrast agent is selected to producean increase in signal intensity under magnetic resonance imaging (MRI).An additional contrast agent may also be sealed within the chamber toprovide visibility under another imaging modality, such as computedtomographic (CT) imaging or ultrasound imaging.

In this way, certain advantages may be realized. For instance, acontrast agent selected to produce an increase in signal intensity in anMR imaging modality may produce good visualization characteristicswithout also producing an excessive artifact and without interferingwith MR spectroscopy or diffusion imaging. Producing an increase insignal intensity in an MR imaging modality may be particularlybeneficial in certain contexts, such as, for example, imaging of breasttissue. Most conventional markers appear as a signal void in MR imaging.The heterogeneous nature of breast tissue makes small signal voidsdifficult to identify. By producing an increase in signal intensity,i.e., a bright area, in MR imaging, the implantable tissue markersdisclosed herein may be easier to see than conventional markers.

The following description of various embodiments implemented in thecontext of imaging certain types of tissue is to be construed by way ofillustration rather than limitation. This description is not intended tolimit the invention or its applications or uses. For example, whilevarious embodiments are described as being implemented in the context ofimaging breast tissue, it will be appreciated that the principles of thedisclosure are applicable to other contexts, such as image registrationduring image guided therapeutic procedures. In further examples, whilevarious embodiments are described as being implemented in the context ofimaging breast tissue, it will be appreciated that the principles of thedisclosure are applicable to other anatomical sites, such as prostate,brain, spinal, and other anatomical sites.

In the following description, numerous specific details are set forth inorder to provide a thorough understanding of various embodiments. Itwill be apparent to one skilled in the art that some embodiments may bepracticed without some or all of these specific details. In otherinstances, well known components and process steps have not beendescribed in detail.

Referring now to the drawings, FIG. 1 is a sectional view illustratingan example implantable radiographic marker 100 according to oneembodiment. A tube 102 is formed from a nonbiodegradable radiopaquesolid material, such as glass, plastic, carbon fiber, or silicone. Forexample, the tube 102 may be formed from LEXAN® polycarbonate resin,commercially available from General Electric Company, headquartered inPittsfield, Mass. The tube 102 is preferably sized for insertion via abiopsy cannula. For example, in one particular implementation, the tube102 has a major dimension of approximately 3-4 mm and a minor dimensionof approximately 1-2 mm.

The tube 102 defines two end portions 104 and 106, at least one of whichis initially open. A chamber 108 is defined within the tube 102 betweenthe two end portions 104 and 106. One or more contrast agents 110 areintroduced into the chamber 108. The end portions 104 and 106 are thensealed, for example, using a sealant 112 such as epoxy. In someembodiments, a permanent biocompatible adhesive such as cyanoacrylateserves as the sealant 112.

The visual representation of the contrast agents 110 in FIG. 1 isintended only to distinguish the contrast agents 110 from the chamber108 in which they are disposed. According to various embodiments, thecontrast agents 110 can be implemented as a gas, gel, or liquid, or as acombination of gases, gels, and/or liquids. Each of these materials canbe selected independently to customize the appearance of the marker 100in different imaging modalities and under different conditions, e.g.,with or without contrast, and in various tissue types.

For instance, if the marker 100 is to be visible in magnetic resonance(MR) and computed tomographic (CT) imaging modalities, the chamber 108may contain a mixture of a gadolinium-DTPA MR contrast agent and aniodinated CT contrast agent. The volume of contrast agent 110 in thechamber 108 may be maximized to promote visibility. Visibility is alsopromoted by matching the magnetic susceptibility of the contrast agent110 and the magnetic susceptibility of the tube 102. If it is furtherdesired that the marker 100 be visible in an ultrasound imagingmodality, the chamber 108 may also contain a gas bubble.

In some embodiments, the tube 102 itself, rather than multiple contrastagents 110, may provide visibility in certain imaging modalities. Forexample, the tube 102 may be made of a radiopaque polymer that providescontrast in X-ray imaging modalities. As another example, a differencein acoustic impedance between the tube 102 and the material in thechamber 108 will cause the marker 100 to reflect ultrasound waves,thereby promoting visibility in an ultrasound imaging modality. Further,if the magnetic susceptibility of the tube 102 is similar to that of thematerial in the chamber 108 and to that of the surrounding tissue,visibility in MR imaging modalities will be improved due to improvedmagnetic field homogeneity and reduced T₂ ^(*) artifact.

In one particular embodiment, the marker 100 is formed by cutting aglass micropipette, commercially available from Fisher Scientific,headquartered in Hampton, N.H., to the desired length, e.g., 4 mm, toform the tube 102. The micropipette has an outer diameter appropriatefor insertion via a biopsy cannula, e.g., 2 mm.

Contrast agents 110 are then introduced into the chamber 108 defined bythe tube 102. In one particular embodiment, for example, an MR contrastagent and a CT contrast agent are combined, and the liquid mixtureresulting from this combination is injected into the micropipette via asyringe of appropriate gauge, e.g., 25 ga. The MR contrast agent may beimplemented as a gadolinium-based MR contrast agent, such as MAGNEVIST®MR contrast agent, commercially available from Berlex, headquartered inMontville, N.J. Other MR contrast agents include, but are not limitedto, OMNISCAN™ MR contrast agent, commercially available from GEHealthcare, headquartered in Chalfont St. Giles, United Kingdom,PROHANCE® MR contrast agent, and OPTIMARK® MR contrast agent,commercially available from Tyco Healthcare/Mallinckrodt, Inc.,headquartered in St. Louis, Mo. The CT contrast agent may be implementedas an iodinated CT contrast agent, such as OMNIPAQUE™ CT contrast agent,commercially available from GE Healthcare, headquartered in Chalfont St.Giles, United Kingdom. Other CT contrast agents include, but are notlimited to, HEXABRIX®, TELEBRIX®, and CONRAY® CT contrast agents,commercially available from Tyco Healthcare/Mallinckrodt, Inc.,headquartered in St. Louis, Mo. After the mixture is injected in thechamber 108, the ends of the tube 102 are sealed using a quick-settingepoxy.

Markers 100 of the type illustrated in FIG. 1 and described above havebeen evaluated for visibility in multiple imaging modalities. Markers100 were made according to the above-described procedure and weresuspended in a gelatin phantom. Magnetic resonance imaging (MRI) wasperformed on the gelatin phantom using a Siemens Trio 3T (3 Tesla) humanMRI scanner. The MRI process used T₁-weighted 3D fast low angle shot(FLASH) images, which are typical for MR examinations of breast tissue.In addition, the gelatin phantom was also imaged using a clinical breastX-ray mammography system and a breast ultrasound using standardsettings.

The evaluation of the markers 100 demonstrated that the markers 100 wereclearly visible on the three modalities, namely, MRI, X-ray mammography,and ultrasound. FIGS. 4-6 are images of markers 100 obtained under theMRI, X-ray mammography, and ultrasound modalities, respectively. Themarkers 100 appeared as small signal voids, i.e., dark spots, underlow-resolution MRI (0.8 mm in plane). However, the contrast agent 110 inthe chamber 108 appeared hyperintense, that is, as bright spots, underhigher MRI resolutions, e.g., 0.4 mm in plane. Accordingly, using higherMRI resolutions, the markers 100 are more clearly distinguishable fromsurrounding tissue than conventional markers that appear as signalvoids. The bright signal seen at higher MRI resolutions may beparticularly advantageous in imaging heterogeneous breast tissue, inwhich signal voids may be difficult to see.

In addition to the MRI modality, the markers 100 were also visible inthe X-ray mammography and ultrasound imaging modalities. In the X-raymammography modality, the radiopaque liquid occupying the chamber 108could be seen clearly with distinct edges. In the ultrasound modality,the tube 102 appeared hyperechoic, while the contrast agents 110occupying the chamber 108 appeared dark. In this modality, the markers100 were most easily seen when they were oriented parallel to thetransducer surface. However, the markers 100 could also be detected whenthey were oriented perpendicular to the transducer surface.

According to various embodiments, the contrast agents 110 that aresealed within the chamber 108 can be selected for visibility in any of anumber of imaging modalities. Besides the MR, X-ray, and ultrasoundimaging modalities mentioned above, contrast agents can be selected forvisibility in computed tomographic (CT) X-ray imaging, fluoroscopy,portal film imaging, electronic portal imaging, electrical impedancetomography (EIT), magnetic source imaging (MSI), magnetic resonancespectroscopy (MRS), magnetic resonance mammography (MRM), magneticresonance angiography (MRA), magnetoelectro-encephalography (MEG), laseroptical imaging, electric potential tomography (EPT), brain electricalactivity mapping (BEAM), arterial contrast injection angiography, anddigital subtraction angiography modalities. Nuclear medicine modalitiesinclude positron emission tomography (PET) and single photon emissioncomputed tomography (SPECT). In addition, as additional imagingmodalities are developed in the future, it will be possible to sealcontrast agents within the chamber 108 that are selected for visibilityin such future modalities.

FIG. 2 is a sectional view of another example tissue marker 120according to another embodiment. The tissue marker 120 incorporates anouter capsule 122 formed from a nonbiodegradable radiopaque solidmaterial, such as silicone. The capsule 122 is generally spherical inshape and is preferably sized for insertion via a biopsy cannula. Thecapsule 122 defines an internal chamber 124.

One or more contrast agents 126 are introduced into the chamber 124, forexample, by injecting the contrast agents 126 into the chamber 124. Thevisual representation of the contrast agents 126 in FIG. 2 is intendedonly to distinguish the contrast agents 126 from the chamber 124 inwhich they are disposed. According to various embodiments, the contrastagents 126 can be implemented as a gas, gel, or liquid, or as acombination of gases, gels, and/or liquids. Each of these materials canbe selected independently to customize the appearance of the marker 120in different imaging modalities and under different conditions, e.g.,with or without contrast, and in various tissue types. For instance, ifthe marker 120 is to be visible in magnetic resonance (MR) and computedtomographic (CT) imaging modalities, the chamber 124 may contain amixture of a gadolinium-DTPA MR contrast agent, such as MAGNEVIST® MRcontrast agent, and an iodinated CT contrast agent, such as OMNIPAQUE™CT contrast agent. The volume of contrast agent 126 in the chamber 124may be maximized to promote visibility. Visibility is also promoted bymatching the magnetic susceptibility of the contrast agent 126 and themagnetic susceptibility of the capsule 122. If it is further desiredthat the marker 120 be visible in an ultrasound imaging modality, thechamber 124 may also contain an air bubble. After the mixture isinjected in the chamber 124, the capsule 122 is sealed.

In some embodiments, the capsule 122 itself, rather than multiplecontrast agents 126, may provide visibility in certain imagingmodalities. For example, the capsule 122 may be made of a radiopaquepolymer that provides contrast in X-ray imaging modalities. As anotherexample, a difference in acoustic impedance between the capsule 122 andthe material in the chamber 124 will cause the marker 120 to reflectultrasound waves, thereby promoting visibility in an ultrasound imagingmodality. Further, if the magnetic susceptibility of the capsule 122 issimilar to that of the material in the chamber 124 and to that of thesurrounding tissue, visibility in MR imaging modalities will be improveddue to reduction of T₂ darkening.

FIG. 3 is a sectional view of another example tissue marker 130according to another embodiment. The tissue marker 130 incorporates anouter capsule 132 formed from a nonbiodegradable radiopaque solidmaterial, such as silicone. The capsule 132 is generally spheroid inshape and is preferably sized for insertion via a biopsy cannula. Thecapsule 132 defines an internal chamber 134.

One or more contrast agents 136 are introduced into the chamber 134, forexample, by injecting the contrast agents 136 into the chamber 134. Thevisual representation of the contrast agents 136 in FIG. 3 is intendedonly to distinguish the contrast agents 136 from the chamber 134 inwhich they are disposed. According to various embodiments, the contrastagents 136 can be implemented as a gas, gel, or liquid, or as acombination of gases, gels, and/or liquids. Each of these materials canbe selected independently to customize the appearance of the marker 130in different imaging modalities and under different conditions, e.g.,with or without contrast, and in various tissue types. For instance, ifthe marker 130 is to be visible in magnetic resonance (MR) and computedtomographic (CT) imaging modalities, the chamber 134 may contain amixture of a gadolinium-DTPA MR contrast agent, such as MAGNEVIST® MRcontrast agent, and an iodinated CT contrast agent, such as OMNIPAQUE™CT contrast agent. The volume of contrast agent 136 in the chamber 134may be maximized to promote visibility. Visibility is also promoted bymatching the magnetic susceptibility of the contrast agent 136 and themagnetic susceptibility of the capsule 132. If it is further desiredthat the marker 130 be visible in an ultrasound imaging modality, thechamber 134 may also contain an air bubble. After the mixture isinjected in the chamber 134, the capsule 132 is sealed.

In some embodiments, the capsule 132 itself, rather than multiplecontrast agents 136, may provide visibility in certain imagingmodalities. For example, the capsule 132 may be made of a radiopaquepolymer that provides contrast in X-ray imaging modalities. As anotherexample, a difference in acoustic impedance between the capsule 132 andthe material in the chamber 134 will cause the marker 130 to reflectultrasound waves, thereby promoting visibility in an ultrasound imagingmodality. Further, if the magnetic susceptibility of the capsule 132 issimilar to that of the material in the chamber 134 and to that of thesurrounding tissue, visibility in MR imaging modalities will be improveddue to reduction of T₂ darkening.

The markers 100, 120, and 130 illustrated in FIGS. 1-3 can be used forimaging a location within a patient's body. One or more markers areimplanted near the location via, for example, a biopsy cannula. Themarkers can be implanted using any of a variety of conventionaltechniques, including, but not limited to, non-invasive medicalprocedures, biopsy procedures, injection, and conventional surgicalprocedures. In addition, the markers can be guided to a desiredanatomical site during implantation using one or more imaging modalitiesin which the markers are detectable. For example, implantation can beguided using MRI, CT, ultrasound, or other modalities.

An image of the location is then generated in an MRI modality. Inaddition, another image of the location can be generated in anotherimaging modality, such as a CT X-ray imaging modality. Other imagingmodalities may be employed, such as ultrasound, X-ray, fluoroscopy,electrical impedance tomography, magnetic source imaging (MSI), magneticresonance spectroscopy (MRS), magnetic resonance mammography (MRM),magnetic resonance angiography (MRA), magnetoelectroencephalography(MEG), laser optical imaging, electric potential tomography (EPT), brainelectrical activity mapping (BEAM), arterial contrast injectionangiography, digital subtraction angiography, positron emissiontomography (PET), and single photon emission computed tomography(SPECT).

If multiple imaging modalities are employed, positional information forthe area of the body that was imaged can be determined as a function ofthe images thus generated. For example, the images can be registered soas to align the coordinate systems of the images. In this way, any pointin the imaged area of the body is made to correspond to identicaladdresses in each image. This registration process involves the use ofrigid body transformation techniques, which in three-dimensional imagesrequires knowledge of at least three points in each image. The markersdescribed above may serve as fiducial markers to mark these points inthe images. Accordingly, the fiducial markers can be used to correlatethe spaces in each image, both with respect to physical space and withrespect to the other images. In addition, the fiducial markers provide aconstant frame of reference that is visible in each imaging modality tofacilitate registration.

As demonstrated by the foregoing discussion, various embodiments mayprovide certain advantages, particularly in the context of imagingheterogeneous breast tissue. For instance, the use of a mixture of an MRcontrast agent and a CT contrast agent may promote visibility inmultiple imaging modalities, thus facilitating registering imagesobtained by multimodal imaging procedures. A contrast agent selected toproduce an increase in signal intensity in an MR imaging modality mayproduce good visualization characteristics without also producing anexcessive artifact and without interfering with MR spectroscopy ordiffusion imaging. By producing an increase in signal intensity in MRimaging, the implantable tissue markers disclosed herein may be easierto see than conventional markers.

Because the contrast agents are sealed within the tube or capsule, theyare at least substantially permanent and are not absorbed by thepatient's body. Thus, multimodal imaging using the markers disclosedherein also allows a clinician to monitor an anatomical site over aperiod of time using images from multiple modalities, if desired. If theanatomical site in question requires treatment, the markers can be usedto determine the precise location of the anatomical site and thus guidetherapy. For example, markers can be implanted at a lesion site prior toremoving the lesion to guide the procedure. After the lesion is removed,the markers can be used to monitor the site overtime.

It will be understood by those who practice the embodiments describedherein and those skilled in the art that various modifications andimprovements may be made without departing from the spirit and scope ofthe disclosed embodiments. For example, the markers disclosed herein mayincorporate therapeutic agents, such as radioactive agents,anti-inflammatory agents, anti-microbial agents, hemostatic agents,biocompatible adhesives, proteins, stem cells, or other material. Suchagents may be applied to an external surface of the markers or disposedwithin the internal chambers. Accordingly, the scope of protectionafforded is to be determined solely by the claims and by the breadth ofinterpretation allowed by law.

Referring to FIGS. 7 and 8, additional examples of implantableradiographic markers 200, 300 are shown. The markers 200, 300, invarious examples, can be formed from materials and in manners similar tothose discussed herein.

Referring to FIG. 7, briefly, in some examples, the marker 200 includesa fully implantable, biocompatible container 202 formed from anonbiodegradable solid material and defining an internal chamber 208. Inthis example, the container 202 includes an opening 203. In a furtherexample, the container 202 is substantially vial-shaped. The marker 200,in an example, includes a lid portion 204 configured to be attached tothe container 202 to close the opening 203. In an example, the lidportion 204 is configured to seal the opening 203. In an example, themarker 200 is sized for insertion via a biopsy cannula.

In some examples, one or more contrast agents 210 are introduced intothe chamber 208. The opening 203, in an example, is sealed with the lidportion 204 to seal the contrast agent 210 within the chamber 208. Insome examples, the opening 203 can be sealed in various ways, includingpress-fitting the lid portion 204 within the opening 203 of thecontainer 202, using sealant or epoxy, or using other sealingtechniques, such as, for instance ultrasonic welding of the lid portion204 and the container 202. The visual representation of the contrastagents 210 in FIG. 7 is intended only to distinguish the contrast agents210 from the chamber 208 in which they are disposed. According tovarious examples, the contrast agents 210 can be implemented as a gas,gel, or liquid, or as a combination of gases, gels, and/or liquids. Eachof these materials can be selected independently to customize theappearance of the marker 200 in different imaging modalities and underdifferent conditions, for instance, with or without contrast or invarious tissue types. For instance, various contrast agents 210 orcombinations of contrast agents 210, as described herein with respect toother examples, can be used for different imaging conditions, imagingmodalities, tissue types, etc.

In an example, the marker 200 is formed by injection molding thecontainer 202 and the lid portion 204. In another example, the marker200 can be formed by micromachining. In a further example, the marker200 can be encapsulated by a material, such as, for instance, silicone,PTFE, or another substance capable of performing as described herein.Such encapsulation, in various examples, can improve the seal of themarker 200; improve the bio-compatibility of the marker 200; can improvethe surface properties of the marker 200, for instance, to facilitatedeployment of the marker 200 through trocar or other device; or reducebio-mobility of the marker 200 once it is implanted.

Referring to FIG. 8, briefly, in some examples, the marker 300 includesa fully implantable, biocompatible container 302 formed from anonbiodegradable solid material and defining an internal chamber 308. Inthis example, the container 302 includes two openings 303, 305. In afurther example, the container 302 is substantially tube-shaped. Themarker 300, in an example, includes two lid portions 304, 306 configuredto be attached to the container 302 to close the openings 303, 305. Inan example, the lid portions 304, 306 are configured to seal theopenings 303, 305. In an example, the marker 300 is sized for insertionvia a biopsy cannula.

In some examples, one or more contrast agents 310 are introduced intothe chamber 308. The openings 303, in an example, are sealed with thelid portions 304, 306 to seal the contrast agent 310 within the chamber308. In some examples, the openings 303, 305 can be sealed in variousways, including press-fitting the lid portions 304, 306 within theopenings 303, 305 of the container 302, using sealant or epoxy, or usingother sealing techniques, such as, for instance ultrasonic welding ofthe lid portions 304, 306 and the container 302. The visualrepresentation of the contrast agents 310 in FIG. 8 is intended only todistinguish the contrast agents 310 from the chamber 308 in which theyare disposed. According to various examples, the contrast agents 310 canbe implemented as a gas, gel, or liquid, or as a combination of gases,gels, and/or liquids. Each of these materials can be selectedindependently to customize the appearance of the marker 300 in differentimaging modalities and under different conditions, for instance, with orwithout contrast or in various tissue types. For instance, variouscontrast agents 310 or combinations of contrast agents 310, as describedherein with respect to other examples, can be used for different imagingconditions, imaging modalities, tissue types, etc.

In an example, the marker 300 is formed by injection molding thecontainer 302 and the lid portions 304, 306. In another example, themarker 300 can be formed by micromachining. In a further example, themarker 300 can be encapsulated by a material, such as, for instance,silicone, PTFE, or another substance capable of performing as describedherein. Such encapsulation, in various examples, can improve the seal ofthe marker 300; improve the bio-compatibility of the marker 300; canimprove the surface properties of the marker 300, for instance, tofacilitate deployment of the marker 300 through trocar or other device;or reduce bio-mobility of the marker 300 once it is implanted.

With reference to FIGS. 1-8, further examples include methods ofmanufacturing radiographic markers 100, 120, 130, 200, 300 capable ofbeing permanently implanted in a living human or animal subject. Invarious examples, the fully implantable, biocompatible container 102,122, 132, 202, 302 is formed from a nonbiodegradable solid material. Insome examples, the container 102, 122, 132, 202, 302 is formed to definean internal chamber 108, 124, 134, 208, 308. In some examples, thecontrast agent 110, 126, 136, 210, 310 is sealed within the internalchamber 108, 124, 134, 208, 308. In various examples, the contrast agent110, 126, 136, 210, 310 is configured to produce a change in signalintensity in at least a magnetic resonance (MR) imaging modality withthe marker 100, 120, 130, 200, 300 fully implanted in the subject. In anexample, the solid material of the container 102, 122, 132, 202, 302includes a first magnetic susceptibility and the contrast agent 110,126, 136, 210, 310 includes a second magnetic susceptibility. In afurther example, the solid material and the contrast agent 110, 126,136, 210, 310 are configured such that the first and second magneticsusceptibilities are matched so that the first magnetic susceptibilityis substantially equivalent to the second magnetic susceptibility. Insome examples, the permanently implantable radiographic marker 100, 120,130, 200, 300 is sized and shaped to fit within a lumen of a cannulaconfigured to deliver the marker 100, 120, 130, 200, 300 to a fullyimplanted location within the subject.

In several examples, the method includes at least partially filling theinternal chamber 108, 124, 134, 208, 308 with the contrast agent 110,126, 136, 210, 310. Such filling can be accomplished in various mannersincluding, but not limited to those described herein. In an example, thecontainer 102, 122, 132, 202, 302 can be immersed within the contrastagent 110, 126, 136, 210, 310 to inhibit gas from being sealed withinthe internal chamber 108, 124, 134, 208, 308. In a further example, thecontainer 102, 122, 132, 202, 302 is sealed while the container 102,122, 132, 202, 302 is immersed in the contrast agent 110, 126, 136, 210,310 to further inhibit unwanted materials from being sealed within theinternal chamber 108, 124, 134, 208, 308 of the container 102, 122, 132,202, 302. In an example, the container 102, 122, 132, 202, 302 can beimmersed within a vat, receptacle, tank, etc. of the contrast agent 110,126, 136, 210, 310 in order to lessen the amount of air or another gasfrom being present within the internal chamber 108, 124, 134, 208, 308prior to sealing of the container 102, 122, 132, 202, 302. In someexamples, the internal chamber 108, 124, 134, 208, 308 is at leastpartially filled with the contrast agent 110, 126, 136, 210, 310 withthe container 102, 122, 132, 202, 302 within a chamber filled with a gasother than ambient air to inhibit ambient air from being sealed withinthe internal chamber 108, 124, 134, 208, 308. In an example, the chamberwithin which the container 102, 122, 132, 202, 302 is filled includesair or another gas at a pressure other than ambient pressure. Forinstance, the container 102, 122, 132, 202, 302 can be filled in avacuum, in a high pressure environment, or in a pressure therebetween.In some examples, the internal chamber 108, 124, 134, 208, 308 can befilled with the contrast agent 110, 126, 136, 210, 310 with thecontainer 102, 122, 132, 202, 302 within a chamber substantially filledwith a gas other than air. In a further example, the internal chamber108, 124, 134, 208, 308 can be filled with the container 102, 122, 132,202, 302 within the chamber substantially filled with nitrogen. Forinstance, in certain examples, oxygen (present in air) can beundesirable due to magnetic properties that could make susceptibilitymatching of the marker 100, 120, 130, 200, 300 more difficult than ifoxygen were not present. In this example, filling of the container 102,122, 132, 202, 302 with the contrast agent 110, 126, 136, 210, 310within a nitrogen-filled chamber would cause residual gas bubbles withinthe container 102, 122, 132, 202, 302 to be nitrogen rather than oxygen,which can be more desirable in certain examples due to the differentmagnetic properties of nitrogen than those of oxygen. However, in otherexamples, the presence of oxygen within the container 102, 122, 132,202, 302 can be desirable. In these examples, by adjusting the mixtureof air or other gas or gases, the magnetic susceptibility and,therefore, the MRI visibility, of the marker 100, 120, 130, 200, 300 canbe adjusted.

In some examples, the container 102, 122, 132, 202, 302 is vibratedduring filling to aid in removal of gas bubbles from within the internalchamber 108, 124, 134, 208, 308 prior to sealing of the container 102,122, 132, 202, 302. Such vibration can cause gas bubbles within thecontrast agent 110, 126, 136, 210, 310 to rise out of the contrast agent110, 126, 136, 210, 310 and toward an opening in the container 102, 122,132, 202, 302, so that the gas bubbles can exit the container 102, 122,132, 202, 302 prior to sealing of the container 102, 122, 132, 202, 302.In an example, the container 102, 122, 132, 202, 302 is ultrasonicallyvibrated in order to aid in removal of gas bubbles from within theinternal chamber 108, 124, 134, 208, 308 prior to sealing of thecontainer 102, 122, 132, 202, 302.

The various examples of filling of the container 102, 122, 132, 202, 302described herein can be used to introduce or decrease amounts of variouscontrast agent materials within the internal chamber 108, 124, 134, 208,308 of the container 102, 122, 132, 202, 302, based upon the desired mixof the contrast agent, the desired purity of the contrast agent, thedesired response of the contrast agent in various imaging modalities, orthe like. In this way, the filling environment and/or the contrast agent110, 126, 136, 210, 310 within the container 102, 122, 132, 202, 302 canbe controlled to tune the response of the marker 100, 120, 130, 200, 300in one or more of various imaging modalities. The described examples offilling of the container 102, 122, 132, 202, 302 are meant to beillustrative and are not intended to be limiting. As such, additionaltechniques and methods of filling the container 102, 122, 132, 202, 302are contemplated herein.

In some examples, the method includes mixing a first contrast agentconfigured to produce the change in signal intensity in the MR imagingmodality and a second contrast agent configured to produce a signal inanother imaging modality. In an example, the other imaging modalityincludes a computed tomographic (CT) X-ray imaging modality. In otherexamples, the other imaging modality includes one of an ultrasoundimaging modality, an X-ray imaging modality, a fluoroscopy imagingmodality, an electrical impedance tomographic imaging modality, amagnetic source imaging (MSI) modality, an magnetic resonancespectroscopic (MRS) modality, a magnetic resonance mammographic (MRM)modality, a magnetic resonance angiographic (MRA) modality, amagnetoelectroencephalographic (MEG) modality, a laser optical imagingmodality, an electric potential tomographic (EPT) modality, a brainelectrical activity mapping (BEAM) modality, an arterial contrastinjection angiographic modality, a digital subtraction angiographicmodality, a positron emission tomographic (PET) modality, and a singlephoton emission computed tomographic (SPECT) modality. In an example,the contrast agent 110, 126, 136, 210, 310 includes the mixture of thefirst and second contrast agents. In this example, the mixture of thefirst and second contrast agents is sealed within the internal chamber108, 124, 134, 208, 308. In other examples, any number of contrastagents can be mixed together, depending upon the application for whichthe marker 100, 120, 130, 200, 300 is to be used. In an example, thefirst contrast agent includes a paramagnetic material. In anotherexample, the first contrast agent includes gadolinium. In a furtherexample, the second contrast agent includes iodine. In various examples,the contrast agent 110, 126, 136, 210, 310 includes at least one of agas material, a liquid material, or a gel material.

In another example, the method includes sealing a therapeutic agentwithin the internal chamber 108, 124, 134, 208, 308.

In an example, the method includes forming the container 102, 122, 132,202, 302 from a solid material configured to produce a signal in animaging modality other than MR, including, but not limited to otherimaging modalities described herein.

In various examples, the method includes forming the container 102, 122,132, 202, 302 in various ways. In an example, the container 102, 122,132, 202, 302 is molded. In a further example, the container 102, 122,132, 202, 302 is injection molded. In a still further example, thecontainer 102, 122, 132, 202, 302 is micromachined. The above examplesare intended to be illustrative, not limiting, as it is contemplatedthat the container 102, 122, 132, 202, 302 can be formed in manners orusing techniques other than those described herein, depending uponfactors including the materials, size, shape, etc. of the marker 100,120, 130, 200, 300.

In such examples, the container 102, 122, 132, 202, 302 can be formedfrom various materials. In some examples, the container 102, 122, 132,202, 302 is formed from a polymeric material. In a further example, thecontainer 102, 122, 132, 202, 302 is formed from a polyether material.In still further examples, the container 102, 122, 132, 202, 302 isformed from a material including at least one of polytetrafluoroethylene(PTFE), polyether ether ketone (PEEK), polysulfone, polyurethane, andpolyethylene. In another example, the container 102, 122, 132, 202, 302is formed from a silicone-based material. The above examples areintended to be illustrative, not limiting, as it is contemplated thatthe container 102, 122, 132, 202, 302 can be formed from materials otherthan those described herein, depending upon the use and desiredproperties of the marker 100, 120, 130, 200, 300.

In some examples, the method includes forming the tube 102 defining thefirst and second end portions 104, 106. In an example, the contrastagent 110 is sealed within the internal chamber 108 includes at leastsubstantially sealing the first and second end portions 104, 106 usingthe biocompatible adhesive 112. In further examples, the tube 102 isformed from a solid material including at least one of a glass material,a ceramic material, a polymer material, silicone, or carbon fiber.

In some examples, the method includes forming a vial-shaped portion 202of the container 202. In this example, the vial-shaped portion 202includes the opening 203. In an example, the lid portion 204 of thecontainer 202 is also formed. In this example, the lid portion 204 ofthe container 202 is configured to be attached at the opening 203 of thevial-shaped portion 202 of the container 202.

In some examples, the method includes forming a first portion 302including at least two openings 303, 305. In this example, second andthird portions 304, 306 are formed and are configured to be attached tothe first portion 302 at the at least two openings 303, 305. In anexample, the first portion 302 is substantially tube-shaped. In anexample, the second and third portions 304, 306 are attached at therespective openings 303, 305 of the first portion 302 to seal thecontrast agent 310 within the internal chamber 308. In other examples,the first portion includes other shapes, such as, but not limited to,substantially spherical, substantially ellipsoidal, substantiallyprismatic, etc. In other examples, the first portion can include more orless than two openings.

In some examples, the method includes coating the marker 100, 120, 130,200, 300 to encapsulate the marker 100, 120, 130, 200, 300. In anexample, the marker 100, 120, 130, 200, 300 is fully encapsulated with amaterial to improve the seal of the marker 100, 120, 130, 200, 300;improve the bio-compatibility of the marker 100, 120, 130, 200, 300; canimprove the surface properties of the marker 100, 120, 130, 200, 300,for instance, to facilitate deployment of the marker 100, 120, 130, 200,300 through trocar or other device; or reduce bio-mobility of the marker100, 120, 130, 200, 300 once it is implanted. In an example, suchencapsulation hermetically seals the marker 100, 120, 130, 200, 300.Various materials are contemplated for encapsulating the marker 100,120, 130, 200, 300. For instance, in some examples, the marker 100, 120,130, 200, 300 can be coated with a material including at least one ofsilicone or PTFE.

Additional Notes

The above detailed description includes references to the accompanyingdrawings, which form a part of the detailed description. The drawingsshow, by way of illustration, specific embodiments in which theinvention can be practiced. These embodiments are also referred toherein as “examples.” Such examples can include elements in addition tothose shown or described. However, the present inventors alsocontemplate examples in which only those elements shown or described areprovided. Moreover, the present inventors also contemplate examplesusing any combination or permutation of those elements shown ordescribed (or one or more aspects thereof), either with respect to aparticular example (or one or more aspects thereof), or with respect toother examples (or one or more aspects thereof) shown or describedherein.

All publications, patents, and patent documents referred to in thisdocument are incorporated by reference herein in their entirety, asthough individually incorporated by reference. In the event ofinconsistent usages between this document and those documents soincorporated by reference, the usage in the incorporated reference(s)should be considered supplementary to that of this document; forirreconcilable inconsistencies, the usage in this document controls.

In this document, the terms “a” or “an” are used, as is common in patentdocuments, to include one or more than one, independent of any otherinstances or usages of “at least one” or “one or more.” In thisdocument, the term “or” is used to refer to a nonexclusive or, such that“A or B” includes “A but not B,” “B but not A,” and “A and B,” unlessotherwise indicated. In the appended claims, the terms “including” and“in which” are used as the plain-English equivalents of the respectiveterms “comprising” and “wherein.” Also, in the following claims, theterms “including” and “comprising” are open-ended, that is, a system,device, article, or process that includes elements in addition to thoselisted after such a term in a claim are still deemed to fall within thescope of that claim. Moreover, in the following claims, the terms“first,” “second,” and “third,” etc. are used merely as labels, and arenot intended to impose numerical requirements on their objects.

Method examples described herein can be machine or computer-implementedat least in part. Some examples can include a computer-readable mediumor machine-readable medium encoded with instructions operable toconfigure an electronic device to perform methods as described in theabove examples. An implementation of such methods can include code, suchas microcode, assembly language code, a higher-level language code, orthe like. Such code can include computer readable instructions forperforming various methods. The code may form portions of computerprogram products. Further, the code may be tangibly stored on one ormore volatile or non-volatile tangible computer-readable media duringexecution or at other times. These computer-readable media may include,but are not limited to, hard disks, removable magnetic disks, removableoptical disks (e.g., compact disks and digital video disks), magneticcassettes, memory cards or sticks, random access memories (RAMs), readonly memories (ROMs), and the like.

The above description is intended to be illustrative, and notrestrictive. For example, the above-described examples (or one or moreaspects thereof) may be used in combination with each other. Otherembodiments can be used, such as by one of ordinary skill in the artupon reviewing the above description. The Abstract is provided to complywith 37 C.F.R. § 1.72(b), to allow the reader to quickly ascertain thenature of the technical disclosure. It is submitted with theunderstanding that it will not be used to interpret or limit the scopeor meaning of the claims. Also, in the above Detailed Description,various features may be grouped together to streamline the disclosure.This should not be interpreted as intending that an unclaimed disclosedfeature is essential to any claim. Rather, inventive subject matter maylie in less than all features of a particular disclosed embodiment.Thus, the following claims are hereby incorporated into the DetailedDescription, with each claim standing on its own as a separateembodiment. The scope of the invention should be determined withreference to the appended claims, along with the full scope ofequivalents to which such claims are entitled.

1. A method of manufacturing a radiographic marker capable of beingpermanently implanted in a living human or animal subject, the methodcomprising: forming a fully implantable, biocompatible container from anonbiodegradable solid material and defining an internal chamber; andsealing a contrast agent within the internal chamber, the contrast agentconfigured to produce a change in signal intensity in a magneticresonance (MR) imaging modality with the marker fully implanted in thesubject, wherein the solid material of the container includes a firstmagnetic susceptibility and the contrast agent includes a secondmagnetic susceptibility, wherein the solid material and the contrastagent are configured such that the first and second magneticsusceptibilities are matched so that the first magnetic susceptibilityis substantially equivalent to the second magnetic susceptibility,wherein the permanently implantable radiographic marker is sized andshaped to fit within a lumen of a cannula configured to deliver themarker to a fully implanted location within the subject.
 2. The methodof claim 1, comprising mixing a first contrast agent configured toproduce the change in signal intensity in the MR imaging modality and asecond contrast agent configured to produce a signal in another imagingmodality, wherein sealing the contrast agent within the internal chamberincludes sealing the mixture of the first and second contrast agentswithin the internal chamber.
 3. The method of claim 2, wherein the otherimaging modality includes an X-ray based imaging modality.
 4. The methodof claim 1, comprising sealing a therapeutic agent within the internalchamber.
 5. The method of claim 1, wherein forming the containerincludes forming the container from a solid material configured toproduce a signal in an imaging modality other than MR.
 6. The method ofclaim 1, wherein forming the container includes forming a tube definingfirst and second end portions, and wherein sealing the contrast agentwithin the internal chamber includes at least substantially sealing thefirst and second end portions using a biocompatible adhesive.
 7. Themethod of claim 6, wherein forming the container includes forming thetube from a solid material including at least one of a glass material, aceramic material, a polymer material, silicone, or carbon fiber.
 8. Themethod of claim 1, wherein forming the container includes micromachiningthe container.
 9. The method of claim 1, wherein forming the containerincludes injection molding the container.
 10. The method of claim 1,wherein forming the container includes forming a vial-shaped portion ofthe container, the vial-shaped portion including an opening.
 11. Themethod of claim 10, wherein forming the container includes forming a lidportion of the container.
 12. The method of claim 11, wherein sealingthe contrast agent within the internal chamber includes attaching thelid portion of the container at the opening of the vial-shaped portionof the container.
 13. The method of claim 1, wherein forming thecontainer includes: forming a first portion including at least twoopenings; and forming second and third portions configured to beattached to the first portion at the at least two openings.
 14. Themethod of claim 13, wherein sealing the contrast agent within theinternal chamber includes attaching the second and third portions atrespective openings of the first portion.
 15. The method of claim 1,comprising coating the container to encapsulate the container.
 16. Themethod of claim 15, wherein coating the container includes hermeticallysealing the container.
 17. The method of claim 1, comprising at leastpartially filling the internal chamber with the contrast agent.
 18. Themethod of claim 17, wherein at least partially filling the internalchamber includes immersing the container within the contrast agent toinhibit air from being sealed within the internal chamber.
 19. Themethod of claim 17, wherein at least partially filling the internalchamber includes vibrating the container during filling to aid inremoval of gas bubbles from within the internal chamber prior to sealingthe container.
 20. The method of claim 17, wherein at least partiallyfilling the internal chamber includes filling the internal chamber withthe container within a chamber filled with a gas other than ambient airto inhibit ambient air from being sealed within the internal chamber.21. A method of manufacturing a radiographic marker capable of beingpermanently implanted in a living human or animal subject, the methodcomprising: forming a fully implantable, biocompatible container from anonbiodegradable solid material and defining an internal chamber, thecontainer including first and second portions, the first portionincluding at least one opening configured to access the internalchamber; at least partially filling the internal chamber with a contrastagent, the contrast agent configured to produce a change in signalintensity in a magnetic resonance (MR) imaging modality with the markerfully implanted in the subject, wherein the solid material of thecontainer includes a first magnetic susceptibility and the contrastagent includes a second magnetic susceptibility, wherein the solidmaterial and the contrast agent are configured such that the first andsecond magnetic susceptibilities are matched so that the first magneticsusceptibility is substantially equivalent to the second magneticsusceptibility, wherein the permanently implantable radiographic markeris sized and shaped to fit within a lumen of a cannula configured todeliver the marker to a fully implanted location within the subject; andsealing the contrast agent within the internal chamber includingattaching the second portion of the container at the opening of thefirst portion of the container.
 22. The method of claim 21, comprisingmixing a first contrast agent configured to produce the change in signalintensity in the MR imaging modality and a second contrast agentconfigured to produce a signal in another imaging modality, whereinsealing the contrast agent within the internal chamber includes sealingthe mixture of the first and second contrast agents within the internalchamber.
 23. The method of claim 21, wherein forming the containerincludes micromachining the container.
 24. The method of claim 21,wherein forming the container includes injection molding the container.25. The method of claim 21, wherein forming the container includes:forming the first portion including at least two openings; and formingthe second portion and a third portion configured to be attached to thefirst portion at the at least two openings, wherein sealing the contrastagent within the internal chamber includes attaching the second andthird portions at respective openings of the first portion.
 26. Themethod of claim 21, comprising coating the container to encapsulate thecontainer.
 27. The method of claim 21, wherein at least partiallyfilling the internal chamber includes immersing the container within thecontrast agent to inhibit air from being sealed within the internalchamber.
 28. The method of claim 21, wherein at least partially fillingthe internal chamber includes vibrating the container during filling toaid in removal of gas bubbles from within the internal chamber prior tosealing the container.
 29. The method of claim 21, wherein at leastpartially filling the internal chamber includes filling the internalchamber with the container within a chamber filled with a gas other thanambient air to inhibit ambient air from being sealed within the internalchamber.
 30. A method of manufacturing a radiographic marker capable ofbeing permanently implanted in a living human or animal subject, themethod comprising: forming a fully implantable, biocompatible containerfrom a nonbiodegradable solid material and defining an internal chamber;at least partially filling the internal chamber with a contrast agent,the contrast agent configured to produce a change in signal intensity ina magnetic resonance (MR) imaging modality with the marker fullyimplanted in the subject, wherein the solid material of the containerincludes a first magnetic susceptibility and the contrast agent includesa second magnetic susceptibility, wherein the solid material and thecontrast agent are configured such that the first and second magneticsusceptibilities are matched so that the first magnetic susceptibilityis substantially equivalent to the second magnetic susceptibility,wherein the permanently implantable radiographic marker is sized andshaped to fit within a lumen of a cannula configured to deliver themarker to a fully implanted location within the subject, wherein atleast partially filling the internal chamber includes: immersing thecontainer within the contrast agent; and vibrating the container duringfilling to aid in removal of gas bubbles from within the internalchamber prior to sealing the container; and sealing the contrast agentwithin the internal chamber.
 31. The method of claim 30, wherein formingthe container includes micromachining the container.
 32. The method ofclaim 30, wherein forming the container includes injection molding thecontainer.
 33. The method of claim 30, comprising coating the containerto encapsulate the container.
 34. The method of claim 30, whereinforming the container includes forming first and second portions of thecontainer, the first portion including the internal chamber and at leastone opening configured to access the internal chamber; wherein sealingthe contrast agent within the internal chamber includes attaching thesecond portion of the container at the opening of the first portion ofthe container.
 35. The method of claim 34, wherein forming the containerincludes: forming the first portion including at least two openings; andforming the second portion and a third portion configured to be attachedto the first portion at the at least two openings, wherein sealing thecontrast agent within the internal chamber includes attaching the secondand third portions at respective openings of the first portion.